Abstract Proposed is a continuation of a 20 year cohort study of the epidemiology of injection drug use and HIV risk among HIV-uninfected injection drug users (IDUs) in Baltimore, MD known as the ALIVE-2 study. The ALIVE cohort is unique in that it comprises a community-based IDU population of both genders who are largely out of drug treatment, with significant representation of African-Americans and those with limited access to appropriate medical care;these populations have been underrepresented in research on persons at risk for HIV infection. ALIVE-2 has provided critical insight into the dynamics of infection and risk behavior while serving as a comparison group to a parallel cohort of HIV positive IDUs (ALIVE-1, DA04334). Continuation of the ALIVE cohort will allow us to characterize current trends in the incidence of blood-borne infections and changing patterns of morbidity and mortality among our unique cohort of aging IDUs. Further, we will consider the broader contextual determinants of risk behavior, disease incidence and mortality. Building upon 20 years of follow-up and experience in studying the health effects of injection drug use, our specific aims are to: 1) Examine temporal trends in risk of HIV and other blood-borne infections (e.g., HCV) among injection drug users in Baltimore, MD;2) Assess mortality and morbidity indices among IDUs according to the burden of blood-borne infections and the spectrum of drug use;3) Characterize the effects of macro-level determinants (e.g., urban redevelopment and drug treatment policy) on HIV risk behaviors, blood-borne infection incidence and morbidity and 4) Continue to serve as a platform for independently funded collaborative investigations of HIV and drug use, including interventions to prevent morbidity and mortality associated with drug use, HIV and HCV infection. To achieve these aims, we will continue follow-up of a cohort of HIV negative IDUs (1000 in active follow-up) with semiannual visits involving interviews and collection of biological specimens for HIV antibody testing and repository. We will implement standardized assessments of chronic disease morbidity that include annual testing of early biological markers of disease as well as detailed medical record abstraction. Further, we will supplement the rich history of individual-level risk data with external data on changes in Baltimore's population, economic situation, and health and drug treatment policies so that we can characterize the effects of macro-level processes on risk behavior and the pathways through which they operate by mapping individuals to their neighborhoods of residence. Multiple external sources including the US Census and the Baltimore Neighborhood Indicators Alliance will be used. To enrich our analyses, we continue a parallel protocol of HIV-infected IDUs (ALIVE-1) to facilitate distinction of the effects of HIV and drug use on our outcomes of interest. The proposed aims will inform HIV prevention and structural interventions and will help to project future health care needs for aging IDUs with a changing spectrum of morbidity. Relevance Injection drug users (IDUs) are at high risk for HIV and hepatitis infections and the long-term complications of these infections as well as drug use itself. The findings from this study will inform HIV prevention and structural interventions and will help to project the future health care needs for aging IDUs with a changing spectrum of morbidity.